PROJECT SUMMARY The goal of this research is to characterize the interaction between the mu-opioid and CB1-cannabinoid receptors during pain. The analgesic properties of opioids are well known, and because of the recent legalization of medicinal cannabis in many US states, cannabis is increasingly being utilized as an analgesic. A growing body of evidence suggests that the cannabinoid and opioid systems interact in several ways that could be of significant therapeutic utility. However, the mechanisms of cannabinoid/opioid interactions, and the abuse potential of combined cannabinoid/opioid administration have yet to be elucidated. Therefore, we propose to characterize the interaction between opioids and cannabinoids in conditions during which these drugs might be used for their analgesic properties; specifically, in inflammatory and neuropathic pain. This five-year, Pathway to Independence project has three Specific Aims. The first Aim (during the mentored K99 phase) will characterize pain-induced adaptations in the CB1 receptor system. The second Aim (during the R00 phase) will determine the efficacy and safety of combined cannabinoid/opioid treatment of inflammatory and neuropathic pain. While the studies in Aim 2 will provide important clinical insight, safe implementation of novel analgesic strategies requires a thorough understanding of the neural mechanisms underlying cannabinoid/opioid interactions. These mechanisms will be uncovered in the third Aim of this proposal, and the experiments therein provide an added benefit of mapping the relatively nebulous periaqueductal gray, using cutting edge optogenetic techniques. The studies in these independent Aims seamlessly blend the skills I propose to acquire with my extensive expertise in the behavioral pharmacology and in vitro physiology of chronic morphine-induced adaptations in the descending pain pathway. The completion of the proposed studies will allow me to accomplish my immediate goal of further characterizing cannabinoid/opioid interactions. It also directly contributes to my long-term goal of developing novel therapies that maximize analgesia while minimizing negative side effects. This Pathway to Independence project also provides me with the critical opportunity to transition from mentored trainee to tenure-track independent investigator. The mentor Jose Moron-Concepcion is the ideal supervisor for this project, as his experience with motivated behavior and molecular biochemistry is critical in carrying my work into the future. As a world leader in the chronic pain field and an innovator in in vitro optogenetics, the co-mentor Robert Gereau is equally well suited to expand my skills to include cutting edge elements that will significantly elevate the impact of my work. Furthermore, the world-class facilities at Washington University will provide an impeccable training environment in which I can complete my goals and successfully transition to independence.